ll

Previews

furin landing site (QTQTNS). Further
studies are required to characterize the
interaction of bona fide bat-borne CoVs
with cells derived from their specific
bat hosts.
Multiple bat species can roost together,
facilitating the transmission and recombi-
nation of bat-borne CoVs. Previous
studies have demonstrated that nutri-
tional and reproductive stress can lead
to increased Hendra virus replication in
Pteropus scapulatus (Plowright et al.,
2008). Using ecological measurements,
Zhou et al. (2021) speculate that tempera-
ture seasonality, evapotranspiration, and
continentality could affect the distribution
of bat species. Most importantly, the au-
thors identified a high richness of rhinolo-
phid bats across much of Southeast Asia
and southern China. This high density of
Rhinolophus bats could potentially facili-
tate intra- and inter-species transmission
and recombination of bat-borne sarbeco-
viruses. As sampling of bat populations
and additional wildlife species intensify,
research will highlight the true diversity
of CoVs that exist in our wildlife
population.
While debate on the origin of SARS-
CoV-2 continues, this recent study by
Zhou et al. (2021) further bolsters the nat-
ural existence of SARS-CoV-2-related vi-
ruses in Rhinolophus bats.
ACKNOWLEDGMENTS
Vaccine and Infectious Disease Organization
(VIDO) receives operational funding for its CL3 fa-
cility (InterVac) from the Canada Foundation for
Innovation through the Major Science Initiatives.
VIDO also receives operational funding from the
Government of Saskatchewan through Innovation
Saskatchewan and the Ministry of Agriculture.
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j.cell.2021.06.008.

Beyond neutralization for BNT162b2 mRNA

vaccination
Payal Damani-Yokota,1 Stephen T. Yeung,2 and Kamal M. Khanna1,3,*
1Department of Microbiology, New York University Langone Health, New York, NY, USA
2Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, USA
3Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA

*Correspondence: kamal.khanna@nyulangone.org
https://doi.org/10.1016/j.chom.2021.06.013

Mounting a robust immune response against SARS-CoV-2 requires neutralization as well as effector T cell
functions. In this issue of Cell Host Microbe, Tauzin et al. characterize the humoral and T cell responses
after a single dose of BNT162b2 mRNA vaccine in individuals with or without previous exposure to SARS-
CoV-2.

We are entering into the 18th month of the
ongoing global severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2)
pandemic that has claimed over 3.8
million reported deaths. As of May 2021,
over 600 million people have been at
least partially vaccinated against corona-
virus disease 2019 (COVID-19), yet bil-
lions are still left vulnerable without ac-
cess to an approved vaccine worldwide.
We are facing unprecedented times
where more than 6 billion people will
require immunization against this virus.
If two or multiple booster doses (against
potential new variants) are required, this

Cell Host & Microbe 29, July 14, 2021 ª 2021 Elsevier Inc. 1033
 ll
would mean more than 12 billion doses
will be necessary to protect against
COVID-19. Therefore, there is an urgent
need for rapid and efficacious vaccine
strategies in order to bring an end to
this worldwide epidemic.
Our knowledge of the precise immuno-
logical parameters that are required for
protection against SARS-CoV-2 is still
evolving, and several recent studies
have provided important clues with
respect to correlates of protection
after either infection or following vaccina-
tion. Antibody-mediated viral neutraliza-
tion has been considered the gold-stan-
dard in determining immune protection
against COVID-19. However, there is no
consensus on the timing and strength
of neutralizing antibodies generated
following vaccination and their ability to
predict immune protection against
COVID-19. Despite a weak neutralization
following a single dose, recent studies
have shown that the antibody response
improves after second vaccination (Goel
et al., 2021). Additionally, a full vaccine
regimen may not be sufficient in gener-
ating strong neutralizing antibodies
against emerging mutations of the virus
such as B.1.3.5 (Planas et al., 2021).
Moreover, neutralization assays have
shown poor viral neutralization in vitro
after one dose of BNT162b2 mRNA
vaccine, although, recent data show
nearly 90% efficacy 2 weeks following a
single dose of mRNA vaccine. Cumula-
tively, these studies suggest that we
have insufficient knowledge of the immu-
nological parameters required for predic-
tion of protection against SARS-CoV-2
infection.
In this issue, Tauzin et al. (2021) expand
our knowledge about the correlates of
immune protection beyond just the
neutralizing antibodies that contribute to-
ward vaccine efficacy after a single dose
administration of an mRNA vaccine,
Pfizer/BioNtech BNT162b2, which en-
codes for a membrane-anchored SARS-
CoV-2 full-length spike (S). In this
comprehensive study, authors use co-
horts of SARS-CoV-2 naive donors or
those previously infected (PI) and
examine their immunological features
prior to and after a single dose of
BNT162b2 vaccine.
The authors found that the naive group
elicited antibodies against receptor-bind-
ing domain and S at levels that were
1034 Cell Host & Microbe 29, July 14, 2021
similar to PI group at 9 months post symp-
tom onset. They further showed that
vaccination also elicited cross-reactive
antibodies against other betacoronavi-
ruses such as SARS-CoV-1 and Midde
East respiratory syndrome (MERS)-CoV
in both cohorts, suggesting a broad
recognition of mRNA vaccines. While a
single dose of BNT162b2 enhanced the
potency of the neutralizing response
against a number of variants, the overall
activity of these neutralizing antibodies
at 3 weeks post vaccination was weak.
In agreement with other published studies
(Collier et al., 2021; Goel et al., 2021), Tau-
zin et al. (2021) found that while the overall
neutralization activity appeared weak in
the naive group after one dose of vaccina-
tion, Fc-mediated effector functions
seemed robust based on the antibody-
dependent cell-mediated cytotoxicity
(ADCC) assays. This suggests the possi-
bility that the production of antibodies
with Fc-mediated effector functions with
low neutralizing capacity can still provide
effective protection and implicates a
role for phagocytes and natural killer
cells in mediating protection (Butler
et al., 2021). In addition to humoral
immunity, by using T cell receptor-depen-
dent activation-induced marker (AIM)
assays as well as intracellular cytokine
staining (ICS), they found a significant
increase in CD4+, cTfh, and CD8+ T cell
responses in the naive group following
a single dose of vaccine. A further
deep profiling of T cells revealed that PI
group exhibited elevated S-specific
CD8+ T cells and CD4+ T cells that also
co-expressed CD40L, IFNg with some-
times co-expression of tumor necrosis
factor alpha, CD107a, and interleukin-2.
Finally, authors created prediction
models based on humoral responses
before vaccination that could provide
cues toward inducing and boosting im-
mune responses following a single dose
of mRNA vaccine. Interestingly, the hu-
moral and cell mediated immune
response in PI individuals immunized by
a single dose of mRNA vaccine was com-
parable to those who received two doses
without previous exposure to SARS-CoV-
2. Recent studies have shown that a sec-
ond dose of vaccine in PI group fails to
augment B cell or T cell responses
(Ebinger et al., 2021; Goel et al., 2021;
Saadat et al., 2021; Samanovic et al.,
2021). Thus, this finding by Tauzin et al.
Previews
(2021) and others suggests that providing
a second dose of vaccine to previously in-
fected individuals is not necessary with
regards to enhancing neutralization,
which will make more doses available for
nations with limited accessibility to vac-
cines. However, further clinical studies
are required to provide definitive insights
into the effectiveness of administering
two doses in PI group. This is because a
second dose in the PI group may yet
help refine the immune repertoire by
enhancing memory T, B cells, or plasma
cells in a way that are not quantitively
boosted.
Overall, Tauzin et al. (2021) provide
a framework for investigating effector
functions and looking beyond the
neutralizing antibodies in response to
vaccinations. This study is highly rele-
vant at the moment considering the
number of newly emerging variants
being identified in different parts of
the world such as P.1, B.1.6.1.7, and
B.1.617.2 (a.k.a. Delta) variants. In addi-
tion to efficacy of mRNA vaccines, there
have been no comprehensive clinical re-
ports showing the efficacy of single or
two dose regimens of AstraZeneca/Cov-
ishield or Covaxin to elicit neutralization
or cellular responses against those vari-
ants. It is likely that a robust immune
protection can be elicited by using a het-
erologous vaccination approach by
combining mRNA and adenovirus-based
vaccines with minimal side effects (Shaw
et al., 2021).
The road ahead
In this issue of Cell Host Microbe, Tauzin
et al. (2021) provide a prediction model
for detecting humoral and cellular im-
mune protection following a single dose
of Pfizer/BioNtech BNT162b2 mRNA
vaccine in virus-naive and PI groups.
Particularly striking, Tauzin et al. (2021)
report the enhancement of cellular re-
sponses even with weak detectable
neutralization suggesting another param-
eter to detect immune protection
following administration of mRNA vac-
cines. However, there are still a number
of unknowns toward understanding the
correlates of immune protection. It is
now widely accepted that the majority
of COVID-19 pathology stems from an
immune overdrive long past viral clear-
ance. To this end, there is a poor under-
standing of the innate immune response

Previews
in the lung and the contributions of
phagocytes toward inflammation and
persisting tissue damage. It is also un-
clear which type of antibodies are being
generated in response to vaccination,
such as the isotypes of immunoglobulin
G. This is critical to evaluate character-
ization of appropriate Fc-dependent
effector functions and subsequent cura-
tion of anti-viral immune response. There
is little clarity about the strength and
quality of antibodies generated in those
individuals that have previously experi-
enced a severe disease against those
with moderate symptoms. This is a crit-
ical gap in our understanding regarding
the level of protection provided by natural
infection and thereby a requirement for a
single versus two dose regimen. Studies
have also shown that even when the anti-
body levels were low following a natural
infection, a single dose remarkably
elevated these levels but did not improve
after a second dose, which may be
because long-lived bone marrow-derived
plasma cells can provide immediate pro-
tection against SARS-CoV2 even when
antibody levels were low in PI patients
(Turner et al., 2021). All these reports
collectively suggest that low antibody
levels are insufficient to conclude lack of
immune protection being afforded since
plasma and T cell responses are
maintained even with low detectable
antibodies.
In order to win the fight against COVID-
19, there needs to be unprecedented con-
cert of policy makers and scientists com-
ing together to engineer strategies that
are safe and efficacious against the exist-
ing and newly emerging mutant variants.
With regards to providing broader protec-
tion against COVID-19, we will need to
extend the use of vaccines in a manner
that protects individuals as well as the
general populous such that those most
vulnerable will be protected. Recent
studies have reported about vaccine effi-
cacy, albeit in narrow pools of clinical
data from specific geography, with co-
horts of patients from selected gender
and genetic backgrounds. While these
data seem scattered, this is to our
advantage considering the cumulative
intelligence being accumulated from
each individual study that provides im-
pactful insights into cohesively untangling
the complexity of the infectivity of viral
variants, their transmission rate, and
the arsenal of host immune system
against them.
ACKNOWLEDGMENTS
The work of Khanna laboratory is funded by the
National Institute of Allergy and Infectious Dis-
eases (NIAID) grants AI143861 and AI143861-
02S1. The authors would like to thank Dr. Ramin
Herati, Department of Medicine and Microbiology
at NYU Grossman School of Medicine for critically
reading the manuscript and for helpful discussions.
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